Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the invention relates to new benzonaphthyridine N-oxides which are used in the pharmaceutical industry for the manufacture of medicaments.
• the invention thus relates to compounds of the formula I
• R1 is 1-4C-alkyl
• R2 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy
• R3 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or wholly or predominantly fluorine-substituted 1-4C-alkoxy, or wherein
• R2 and R3 together represent a 1-2C-alkylenedioxy group
• R4 represents a phenyl radical substituted by R5, where
• R5 represents a tetrazol-5-yl radical substituted by a radical R6, where
• R6 is hydrogen, 1-10C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where
• Ar represents a phenyl radical which is unsubstituted or substituted by R7 and / or R8, and
• R7 and R8 independently of one another denote 1-4C-alkyl or 1-4C-alkoxy, as well as the salts of these compounds.
• 1-4C-alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radical.
• 1-4C-alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
• 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
• 3-7C-Cycloalkylmethoxy stands for Cyclopropylmethoxy, Cyclobutylmethoxy, Cyclopentylmethoxy, Cyclohexylmethoxy and Cycloheptylmethoxy, of which Cyclopropylmethoxy, Cyclobutylmethoxy and Cyclopentylmethoxy are preferential.
• Examples of completely or predominantly fluorine-substituted 1-4C-alkoxy include 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1,2,2-trifluoroethoxy, in particular 1, 1, 2, Called 2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and preferably the difluoromethoxy.
• 1-2C-Alkylenedioxy stands for example for the methylenedioxy- (-0-CH 2 -0-) and the ethylenedioxy radical (-0-CH 2 -CH 2 -0-).
• 1-10C-alkyl stands for straight-chain or branched alkyl radicals with 1 to 10 carbon atoms.
• Examples include decyl, nonyl, octyl, heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), Pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl , Ethyl and the methyl radical.
• 3-7C-Cycloalkyl stands for the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radical.
• the 5-7C-cycloalkyl radicals cyclopentyl, cyclohexyl and cycloheptyl are preferred.
• 3-7C-Cycloalkylmethyl stands for a methyl radical which is substituted by one of the above 3-7C-Cycloalkylreste.
• Examples include the cyclopentylmethyl and cyclohexylmethyl radicals.
• Ar-1-4C-alkyl represents one of the above-mentioned 1-4C-alkyl radicals which is substituted by one of the aryl radicals defined above. Examples include the p-methoxybenzyl, phenethyl and benzyl radicals.
• Suitable salts for compounds of the formula I — depending on substitution — are all acid addition salts or all salts with bases. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases commonly used in galenics. Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyi) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether
• salts with bases can also be used.
• alkali lithium, sodium, potassium
• calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts may be mentioned, the bases also being used here in salt production equimolar or a different ratio.
• Pharmacologically incompatible salts which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
• the compounds according to the invention and their salts if they are isolated, for example, in crystalline form, can contain different amounts of solvents.
• the invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
• R1 means 1-2C-alkyl
• Fluorine-substituted 1-4C-alkoxy means R3 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or entirely or predominantly by
• R4 represents a phenyl radical substituted by R5, where R5 represents a tetrazol-5-yl radical substituted by a radical R6, where R6 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl, where Ar is an unsubstituted or substituted by R7 and / or R8 phenyl radical, and R7 and R8 independently of one another 1- 4C-alkyl or 1-4C-alkoxy mean, as well as the salts of these compounds.
• R1 means methyl
• Fluorine substituted 1-2C-alkoxy means, R3 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or entirely or predominantly by
• Fluorine-substituted 1-2C-alkoxy means R4 is a phenyl radical substituted by R5, where R5 is a tetrazol-5-yl radical substituted by a radical R6, where R6 is hydrogen, 1-7C-alkyl, 5-7C-cycloalkyl, 3- 7C-cycloalkylmethyl or Ar-1-2C-alkyl, where Ar is an unsubstituted or substituted by R7 phenyl radical, and R7 is 1 -2C-alkyl or 1 -2C-alkoxy, and the salts of these compounds.
• Preferred compounds of formula I are those in which
• R1 means methyl
• R2 means 1-4C-alkoxy
• R3 means 1-4C-alkoxy
• R4 represents a phenyl radical substituted by R5, where
• R5 represents a tetrazol-5-yl radical substituted by a radical R6, where
• R6 is hydrogen, 1-7C-alkyl, cyclohexylmethyl or 4-methoxybenzyl, and the salts of these compounds.
• R1 means methyl
• R2 ethoxy means
• R3 means methoxy or ethoxy
• R4 represents a phenyl radical substituted by R5, where
• R5 represents a tetrazol-5-yl radical substituted by a radical R6, where
• R6 is 1-4C-alkyl, and the salts of these compounds.
• the compounds of the formula I are chiral compounds with chiral centers in positions 2, 4a and 10b.
• the numbering of the compounds of formula I is shown in formula la.
• the invention relates to all eight possible enantiomers in any mixing ratio to one another.
• Preferred are the compounds of formula I in which the hydrogen atoms in positions 4a and 10b are in the cis position relative to one another.
• particular preference is given to those compounds of the formula I which have the same absolute configuration in positions 4a and 10b as the compound (-) - cis-4-amino-3- (3-ethoxy-4-methoxyphenyl) which can be used as the starting product.
• the tetrazol-5-yl radical R5 of the compounds of the formula I can be attached to the phenyl radical R4 both in the ortho, meta and in the para position to the benzonaphthyridine ring.
• Preferred compounds of the formula I are those in which the tetrazol-5-yl radical R5 is bonded to the phenyl radical R4 in the meta or para position to the benzonaphthyridine ring.
• particular preference is given to the compounds of the formula I in which the tetrazol-5-yl radical R5 is bonded in the para position.
• the invention therefore also relates to the 1 H and 2H-tetrazol-5-yl compounds of the formula I which are substituted by a radical R6 (R6 ⁇ H), both in pure form and in any mixing ratio.
• R6 substituents R6
• the invention further relates to a process for the preparation of the compounds of the formula I, in which R1, R2, R3 and R4 have the meanings indicated above, and their salts.
• the process is characterized in that compounds of the formula II
• R1, R2, R3 and R4 have the meanings given above, subject to N-oxidation and, if desired, subsequently converting the compounds of the formula I obtained into their salts, or if desired subsequently obtained salts of the compounds of the formula I into the free compounds transferred.
• the N-oxidation takes place in a manner familiar to the person skilled in the art, e.g. with the help of hydrogen peroxide in methanol or with the help of m-chloroperoxibenzoic acid in dichloromethane at room temperature.
• the person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge.
• R4 is a phenyl radical which is substituted by a 1 H- or 2H-tetrazol-5-yl radical R5, for example from the corresponding compounds of the formula II in which R4 represents a phenyl radical substituted by a cyano group, can be prepared by reaction with an alkali metal azide and an ammonium halide (for example ammonium chloride). Corresponding reactions are e.g. in J. Med. Chem. 1993, 36, 3246.
• the compounds of the formula II obtained in this way can be converted into further compounds of the formula II by an alkylation reaction, the hydrogen on the tetrazol-5-yl radical being replaced by one of the radicals mentioned for R6, with the exception of hydrogen.
• the alkylation reactions are advantageously carried out analogously to the methods known to the person skilled in the art, e.g. by reaction of the 1 H or 2H tetrazole compounds of the formula II with compounds of the formula R6-X in the presence of a base, where R6 has the meanings given above - except hydrogen - and X is a suitable leaving group such as a chlorine, bromine or iodine atom or represents an alkyl sulfate residue.
• the 1- and 2-substituted tetrazole regioisomer mixtures usually formed in the alkylation are separated by methods known to the person skilled in the art, such as crystallization or chromatography on suitable support materials.
• An analogous alkylation of tetrazoles and separation of the regioisomers is described, for example, in J. Med. Chem. 1996, 39, 2354.
• cyclocondensation is carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (for example as described in J. Chem. Soc, 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, Phosphorus pentoxide, thionyl chloride or preferably phosphorus oxytrichloride, in a suitable inert solvent, e.g.
• a chlorinated hydrocarbon such as chloroform
• a cyclic hydrocarbon such as toluene or xylene
• another inert solvent such as acetonitrile
• an excess of condensing agent preferably at elevated temperature, in particular at the boiling point of the solvent or Condensing agent.
• Enantiomerically pure compounds of the formula II can be separated in a known manner (for example by preparing and separating corresponding diastereoisomeric compounds) or can be prepared by stereoselective synthesis methods. Such separation processes and synthesis methods are described for example in EP 247 971 and in DE 42 17 401.
• R1, R2 and R3 have the meanings given above
• R4-CO-Y in which R4 has the meanings indicated above
• Y is a suitable transition group, preferably represents a chlorine atom, accessible.
• benzoylation is carried out according to the Einhorn method, the Schotten-Baumann variant or as described in J. Chem. Soc. (C), 1971, 1805-1808.
• R4-COOH in which R4 has the meanings given above, are either known or can be obtained in a manner known to the person skilled in the art from 2-, 3- or 4-cyanobenzoic acid alkyl esters, e.g. by reaction with alkali azides and an ammonium halide (e.g. ammonium chloride) to give 2-, 3- or 4- (1 H- or 2H-tetrazol-5-yl) benzoic acid alkyl esters which are unsubstituted in the tetrazole part.
• an ammonium halide e.g. ammonium chloride
• these intermediates - as described above for the 1 H or 2H tetrazole compounds of the formula II or in the abovementioned literature - can be converted by alkylation with compounds of the formula R6-X in the presence of a base into R4-carboxylic acid alkyl esters in which R4 represents a phenyl radical substituted by R5, R5 represents a 1 H- or 2H-tetrazol-5-yl radical substituted by a radical R6 and R6 is not hydrogen but has one of the other meanings given above for R6.
• the R4-carboxylic acid alkyl esters are converted into the free carboxylic acids R4-COOH by alkaline or acidic hydrolysis conditions familiar to the person skilled in the art.
• the substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
• Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic Alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is subsequently added will give.
• a suitable solvent e.g. a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic Alcohol such as
• mp stands for melting point, h for hour (s), RT for room temperature, SF for molecular formula, MG for molecular weight, TLC for thin layer chromatography, calc. for calculated, found for found.
• mp stands for melting point, h for hour (s), RT for room temperature, SF for molecular formula, MG for molecular weight, TLC for thin layer chromatography, calc. for calculated, found for found.
• the compounds mentioned in the examples and their salts are a preferred subject of the invention.
• the compounds according to the invention have valuable pharmacological properties which make them commercially usable.
• selective inhibitors of types 3 and 4 of cyclic nucleotide phosphodiesterase PDE3, PDE4
• they are suitable on the one hand as bronchial therapeutic agents (for the treatment of airway obstructions due to their dilating and celiac stimulating effect but also due to their respiratory rate and respiratory drive increasing effect) on the other hand for the treatment of diseases of an inflammatory nature, for example the respiratory tract (asthma prophylaxis), the skin, the intestine, the eyes and the joints, which are mediated by mediators such as interferons, members of the tumor necrosis factor family, interleukins, chemokines, colony-stimulating factors, growth factors, lipid mediators (e.g.
• PAF platelet activating factor
• bacterial factors e.g. LPS
• immunoglobulins oxygen radicals and relatives (e.g. nitrogen monoxide NO), biogenic amines (e.g. histamine, serotonin), kinins (e.g. Bradykinin), neurogenic mediators (such as substance P, neurokinin), proteins such as e.g. Granular substances from leukocytes (e.g. cationic proteins from eosinophils) and adherence proteins (e.g. integrins).
• the compounds of the invention have smooth muscle cell relaxing activity, e.g. in the area of the bronchial system, blood circulation, and the urinary tract. Furthermore, they have cilia frequency-increasing effects, e.g. in the bronchial system.
• the compounds according to the invention are notable for low toxicity, good human acceptance, good enteral absorption and high bioavailability, a wide therapeutic range, the absence of significant side effects and good water solubility.
• the compounds according to the invention can be used as therapeutic agents in human and veterinary medicine, for example they can be used for the treatment and prophylaxis of the following diseases: Acute and chronic (in particular inflammatory and allergen-induced) respiratory diseases of various origins (bronchitis, allergic Bronchitis, bronchial asthma, emphysema, COPD); Diseases with restricted ciliary activity or increased demands on ciliary clearance (bronchitis, cystic fibrosis), dermatoses (especially proliferative, inflammatory and allergic types) such as psoriasis (vulgaris), toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, Are simplex, sunburn, pruritus in the genito-anal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyoderma
• the compounds according to the invention can also be used to treat hypertension disorders of various origins, such as pulmonary hypertension and the associated side effects, for the treatment of erectile dysfunction or colic of the kidneys and ureters in connection with kidney stones.
• cAMP-increasing effect they can also be used for diseases of the heart that can be treated by PDE inhibitors, such as heart failure, and as anti-thrombotic substances that inhibit platelet aggregation.
• Another object of the invention is a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases.
• the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.
• the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of diseases, in particular the diseases mentioned.
• the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.
• the invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention.
• Another object of the invention is a commercial product, consisting of a conventional secondary packaging, a primary packaging containing the drug (for example, an ampoule or a blister) and, if desired, a package insert, the drug showing antagonistic activity against cyclic-nucleotide phosphodiesterases of types 3 and 4 and leads to a weakening of the symptoms of diseases which are associated with cyclic nucleotide phosphodiesterases of types 3 and 4, and on the secondary packaging and / or on the package insert of the commercial product on the suitability of the medicinal product for the prophylaxis or treatment of diseases which are in the Connection with cyclic-nucleotide phosphodiesterases of types 3 and 4 are pointed out, and wherein the medicament contains one or more compounds of the formula I according to the invention.
• the secondary packaging, the primary packaging containing the medicament and the package insert otherwise correspond to what the person skilled in the art would regard as the standard for medicaments of this type.
• the substances according to the invention are also suitable for combination with other substances which stimulate cAMP, such as prostaglandins (PGE2, PGI2 or prostacinin) and their derivatives, direct adenylate cyclase stimulators such as forskolin and related substances, or adenylate cyclase indirectly stimulating substances such as catecholamines and adrenergic receptor agonists, in particular beta-mimetics.
• PGE2 prostaglandins
• PGI2 or prostacinin prostacinin
• adenylate cyclase stimulators such as forskolin and related substances
• adenylate cyclase indirectly stimulating substances such as catecholamines and adrenergic receptor agonists, in particular beta-mimetics.
• they develop a synergistic, superadditive effect due to their cAMP degradation-inhibiting effect. This comes e.g. when used in combination with PGE2 to treat pulmonary hypertension.
• the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
• auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
• active substance carriers for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
• the compounds according to the invention are preferably also administered by inhalation.
• these are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them.
• the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application.
• suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
• the pharmaceuticals according to the invention are produced by methods known per se.
• the active ingredients are dosed in the order of magnitude customary for PDE inhibitors.
• topical forms of application such as ointments
• the dose for inhalation is usually between 0.1 and 3 mg per day.
• the usual dose for systemic therapy is between 0.01 and 10 mg per kilogram and day.
• Activation of inflammatory cells is of particular importance when studying PDE4 inhibition at the cellular level.
• An example is the FMLP (N-formyl-methionylleucylphenylalanine) -induced superoxide production of neutrophil granulocytes, which can be measured as luminol-enhanced chemiluminescence.
• FMLP N-formyl-methionylleucylphenylalanine
• Substances which inhibit chemiluminescence and the cytokine secretion and the secretion of inflammation-increasing mediators on inflammatory cells are those which inhibit PDE4 or PDE3 and PDE4.
• the latter isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation.
• the PDE4 inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes.
• PDE activity was determined according to Thompson et al. (1) with some modifications (2).
• the test samples contained 40 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 0.5 ⁇ M cAMP or cGMP, [ 3 H] cAMP or
• [ 3 H] cGMP (approx. 50,000 cpm / sample), the PDE isoenzyme-specific additives described in more detail below, the indicated concentrations of inhibitor and an aliquot of the enzyme solution for a total sample volume of 200 ⁇ l.
• Stock solutions of the compounds to be examined in DMSO were prepared in such concentrations that the DMSO content - to avoid influencing the PDE activity - did not exceed 1% by volume in the test samples. After 5 minutes of pre-incubation at 37 ° C, the reaction was started by adding the substrate (cAMP or cGMP). The samples were incubated for a further 15 min at 37 ° C. The reaction was stopped by adding 50 ⁇ l of 0.2 N HCl.
• Bovine brain PDE1 (Ca2 + / calmodulin-dependent): The inhibition of this isoenzyme was investigated in the presence of Ca 2+ (1 mM) and calmodulin (100 nM) using cGMP as substrate (3).
• PDE2 (cGMP-stimulated) from rat hearts was purified chromatographically [Schudt et al. (4)] and in the presence of cGMP (5 ⁇ M) using cAMP as substrate.
• PDE3 cGMP-inhibited
• PDE5 cGMP-specific
• PDE4 cAMP-specific
• PMNL human polymorphonuclear leukocytes
• the PDE3 inhibitor motapizon (1 ⁇ M) was used to suppress the PDE3 activity emanating from contaminating platelets.
• IC 50 values were determined from the concentration-inhibition curves by nonlinear regression using the GraphPad InPlot TM program (GraphPad Software Inc., Philadelphia, USA).
• Table 1 shows the inhibitory concentrations determined according to point A1 [inhibitory concentrations as -log IC 50 (mol / l)] for compound 1 for various PDE isoenzymes.
• the number of the connection corresponds to the number of the example in the section end products.

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